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Metal Ion Controlled Self-Assembly of a Chemically Reengineered Protein Drug Studied by Small-Angle X-ray Scattering

Författare:
  • Jesper Nygaard
  • Henrik K. Munch
  • Peter W. Thulstrup
  • Niels J. Christensen
  • Thomas Hoeg-Jensen
  • Knud J. Jensen
  • Lise Arleth
Publiceringsår: 2012
Språk: Engelska
Sidor: 12159-12170
Publikation/Tidskrift/Serie: Langmuir
Volym: 28
Nummer: 33
Dokumenttyp: Artikel
Förlag: American Chemical Society

Sammanfattning

Precise control of the oligomeric state of proteins is of central importance for biological function and for the properties of biopharmaceutical drugs. Here, the self-assembly of 2,2'-bipyridine conjugated monomeric insulin analogues, induced through coordination to divalent metal ions, was studied. This protein drug system was designed to form non-native homo-oligomers through selective coordination of two divalent metal ions, Fe(II) and Zn(II), respectively. The insulin type chosen for this study is a variant designed for a reduced tendency toward native dimer formation at physiological concentrations. A small-angle X-ray scattering analysis of the bipyridine-modified insulin system confirmed an organization into a novel well-ordered structure based on insulin trimers, as induced by the addition of Fe(II). In contrast, unmodified monomeric insulin formed larger and more randomly structured assemblies upon addition of Fe(II). The addition of Zn(II), on the other hand, led to the formation of small quantities of insulin hexamers for both the bipyridine-modified and the unmodified monomeric insulin. Interestingly, the location of the bipyridine-modification significantly affects the tendency to hexamer formation as compared to the unmodified insulin. Our study shows how combining a structural study and chemical design can be used to obtain molecular understanding and control of the self-assembly of a protein drug. This knowledge may eventually be employed to develop an optimized in vivo drug release profile.

Disputation

Nyckelord

  • Medicine and Health Sciences

Övriga

Published
Yes
  • ISSN: 0743-7463

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